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EP2575457B1 - Composition pharmaceutique à base de duloxétine destinée à la voie orale - Google Patents

Composition pharmaceutique à base de duloxétine destinée à la voie orale Download PDF

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Publication number
EP2575457B1
EP2575457B1 EP10852078.4A EP10852078A EP2575457B1 EP 2575457 B1 EP2575457 B1 EP 2575457B1 EP 10852078 A EP10852078 A EP 10852078A EP 2575457 B1 EP2575457 B1 EP 2575457B1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
delayed release
release pharmaceutical
duloxetine
cellulose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Not-in-force
Application number
EP10852078.4A
Other languages
German (de)
English (en)
Other versions
EP2575457A4 (fr
EP2575457A1 (fr
Inventor
Bandi Parthasaradhi Reddy
Podili Khadgapathi
Sanikommu Venkata Ramana Reddy
Kalidindi Praveen Kumar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hetero Research Foundation
Original Assignee
Hetero Research Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hetero Research Foundation filed Critical Hetero Research Foundation
Publication of EP2575457A1 publication Critical patent/EP2575457A1/fr
Publication of EP2575457A4 publication Critical patent/EP2575457A4/fr
Application granted granted Critical
Publication of EP2575457B1 publication Critical patent/EP2575457B1/fr
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core

Definitions

  • the present invention relates to an oral pharmaceutical composition of duloxetine or pharmaceutically acceptable salts thereof.
  • the invention also relates to a delayed release composition of duloxetine comprising a core containing duloxetine, an optional separating layer, an enteric layer and an optional finishing layer.
  • Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), effective for major depressive disorder and it is as effective as venlafaxine in generalized anxiety disorder.
  • SSNRI serotonin and norepinephrine reuptake inhibitor
  • Duloxetine is chemically (+)-( S )- N- methyl- ⁇ -(1-naphthyloxy)-2-thiophene propylamine, and commonly used as its hydrochloride salt.
  • duloxetine will refer to the hydrochloride salt of the S-enantiomer unless otherwise specified.
  • Duloxetine hydrochloride has the following formula.
  • Duloxetine is commercially available as capsules containing delayed release pellets under the trade name CYMBALTATM in the United States. It has been approved by the FDA for the treatment of major depressive disorder, treatment of generalized anxiety disorder, management of neuropathic pain associated with diabetic peripheral neuropathy and management of fibromyalgia. Duloxetine is also commercially available as hard gastro-resistant capsules under the trade names CYMBALTATM and YENTREVETM in Europe. It has been approved by EMEA for the treatment of major depressive disorder, treatment of diabetic peripheral neuropathic pain in adults and treatment of generalized anxiety disorder under the brand name CYMBALTATM and for the treatment of moderate to severe stress urinary incontinence in woman under the trade name YENTREVETM.
  • duloxetine being an acid-labile substance is very much susceptible to degradation in the acidic environment of the stomach. Therefore duloxetine is formulated as an enteric coated dosage form to protect it from acid degradation.
  • US Patent No. 5,508,276 discloses an enteric duloxetine pellet comprising hydroxypropylmethyl cellulose acetate succinate (HPMCAS) as an enteric coating polymer.
  • HPMCAS hydroxypropylmethyl cellulose acetate succinate
  • the '276 patent also discloses that the HPMCAS should be neutralized, for example, with ammonia to facilitate its dissolution.
  • duloxetine was found to react with many enteric coatings to form a slowly soluble or insoluble coating. This may lead to a disadvantageous drug-releasing profile and/or low bioavailability.
  • US patent application no. 2006/0165776 describes an oral pharmaceutical composition comprising a core comprising duloxetine or its pharmaceutically acceptable derivative thereof and the said core comprised of pharmaceutically inert nuclei and duloxetine or its pharmaceutically acceptable derivative thereof mixed and compressed together, an intermediate layer and an enteric layer comprising one or more enteric polymers; wherein the said composition is free of alkaline reacting compounds.
  • US patent application no. 2007/0292511 discloses a duloxetine hydrochloride delayed release formulation, comprising an inert core, a drug layer comprising duloxetine hydrochloride, a separating layer and an enteric layer comprising at least one of methacrylic acid copolymer and hydroxypropyl methyl cellulose phthalate.
  • US patent application no. 2008/0226711 discloses a delayed release pharmaceutical composition
  • a core comprising an inert core coated with duloxetine, optionally a separating coat on the core and an enteric coat on the core or on the separating coat, wherein the enteric coat comprises hydroxypropyl methylcellulose phthalate (HPMCP) or cellulose acetate phthalate (CAP) or polyvinyl acetate phthalate (PVAP).
  • HPMCP hydroxypropyl methylcellulose phthalate
  • CAP cellulose acetate phthalate
  • PVAP polyvinyl acetate phthalate
  • duloxetine reacts with degradation products or residual free acids present in the enteric polymer such as hydroxypropyl methylcellulose phthalate to form impurities such as phthalamide impurities.
  • the present invention provides a delayed release composition
  • a delayed release composition comprising; inert core, a drug layer comprising duloxetine, an optional separating layer, an enteric layer comprising carboxymethyl ethyl cellulose and an optional finishing layer.
  • the main objective of the invention is to provide a delayed release composition of duloxetine or its pharmaceutically acceptable salts comprising; inert core, a drug layer comprising duloxetine, an optional separating layer, an enteric layer comprising carboxy methyl ethyl cellulose and an optional finishing layer.
  • the main aspect of the present invention is to provide a delayed release formulation comprising:
  • a delayed release pharmaceutical composition of duloxetine or its pharmaceutically acceptable salts comprising:
  • duloxetine is in the form of its hydrochloride salt.
  • the inert core comprises sugar spheres or pellets of microcrystalline cellulose and more preferably, the inert core comprises sugar spheres.
  • the drug layer further comprises one or more pharmaceutically acceptable excipients that do not react adversely with duloxetine.
  • the pharmaceutically acceptable excipients are selected from diluents, binders and disintegrants.
  • the preferable diluent is selected from the group consisting of mannitol, sucrose, sorbitol, starch, modified starches, xylitol, lactose, microcrystalline cellulose, magnesium carbonate, starch, calcium carbonate, dicalcium phosphate, tribasic calcium phosphate, and calcium sulphate.
  • the preferable binder is selected from L-hydroxy propyl cellulose, corn starch, polyvinyl pyrrolidine, hydroxyl propyl methyl cellulose, hydroxyl ethyl cellulose and pre-gelatinized starch.
  • the disintegrant may be preferably selected from croscarmellose sodium, crospovidone, sodium starch glycolate and low substituted hydroxyl propyl cellulose.
  • the pharmaceutically acceptable excipients are selected from sucrose, hydroxy propyl cellulose, hydroxy propyl methyl cellulose, crospovidone, talc and mixtures thereof.
  • the drug layer comprises duloxetine, sugar spheres, hydroxy propyl methyl cellulose, hydroxy propyl cellulose, sucrose extra fine, crospovidone and talc.
  • the drug layer comprises about 15% to about 40% duloxetine, about 30-80% sugar spheres, about 2-10% hydroxy propyl methyl cellulose, about 0-10% hydroxy propyl cellulose, about 0-10% sucrose extra fine, about 1-10% crospovidone and about 1-10% talc, wherein the percentages are by weight of the drug layer.
  • the separating layer between drug layer and enteric layer is optional.
  • the functions of the separating layer, if applied, are to provide a smooth base for the application of the enteric layer, to prolong the pellet's resistance to acid conditions and to improve stability.
  • the preferable separating layer comprises sucrose, hydroxy propyl methyl cellulose and talc.
  • the separating layer is present in an amount of about 5-30% based on the total weight of the formulation.
  • the separating layer is present in an amount of about 10-25% based on the total weight of the formulation.
  • the enteric layer may preferably comprise carboxymethyl ethyl cellulose and povidone.
  • the enteric layer is present in an amount of about 5-30% based on the total weight of the formulation.
  • the enteric layer is present in an amount of about 10-20% based on the total weight of the formulation.
  • the solvent used to make the enteric coating solution is selected from isopropanol, water and mixtures thereof.
  • the preferable solvent is a mixture of isopropanol and water.
  • the preferable ratio of isopropanol and water used in the enteric coating solution is 1:9 to 9:1.
  • a finishing layer is present over the enteric coating layer.
  • the optional finishing layer comprises hydroxypropyl methyl cellulose, talc, polyethylene glycol 400 (PEG-400) and titanium dioxide.
  • the delayed release pharmaceutical composition of duloxetine is in the form of pellets.
  • the film coated duloxetine pellets were then filled into hard gelatin capsules.
  • Example 1 Ingredient Quantity ( mg ) Core Sugar spheres 155.70 Duloxetine hydrochloride 67.30 Hydroxypropyl methyl cellulose 10.00 Hydroxy propyl cellulose 3.00 Sucrose extra fine 3.00 Crospovidone 5.00 Talc 6.00 Purified water q.s Separating layer Sucrose 31.00 Hydroxypropyl methyl cellulose 11.00 Talc 11.00 Purified water q.s Enteric Coating Carboxy methyl ethyl cellulose 39.00 Povidone 3.00 Isopropanol /Water (7:3) q.s Total weight 345.00
  • Example 2 Ingredient Quantity ( mg ) Core Sugar spheres 155.70 Duloxetine hydrochloride 67.30 Hydroxypropyl methyl cellulose 10.00 Sucrose extra fine 3.00 Crospovidone 5.00 Talc 6.00 Purified water q.s Separating layer Sucrose 31.00 Hydroxypropyl methyl cellulose
  • Duloxetine hydrochloride and other inactive ingredients were dispersed in purified water. This dispersion was coated on the sugar spheres in a fluid bed processor.
  • Sucrose and hydroxypropyl methyl cellulose were dissolved in purified water and talc dispersed in to this solution under stirring. This dispersion was coated on the drug loaded spheres in a fluid bed processor.
  • the above coated particles were then coated in fluid bed processor with a solution of carboxymethyl cellulose, povidone in purified water and isopropanol.
  • Hydroxypropyl methyl cellulose, polyethylene glycol, titanium dioxide and talc were added in purified water and this dispersion was coated on the enteric coated pellets in a fluid bed processor.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (14)

  1. Une composition pharmaceutique à libération retardée de duloxétine ou ses sels pharmaceutiquement acceptables comprenant :
    a) un noyau inerte chargé avec de la duloxétine ou ses sels pharmaceutiquement acceptables,
    b) une couche de séparation optionnelle,
    c) un enrobage entérique au-dessus du sous-enrobage avec carboxyméthyléthylcellulose et povidone ; et
    d) une couche de finition facultative.
  2. La composition pharmaceutique à libération retardée de la revendication 1, dans laquelle la duloxétine est sous forme de son sel chlorhydrate.
  3. La composition pharmaceutique à libération retardée de la revendication 1, dans laquelle le noyau inerte comprend des sphères de sucre ou des pellets de cellulose microcrystalline.
  4. La composition pharmaceutique à libération retardée de la revendication 1, dans laquelle la couche de médicament comprend un ou plusieurs excipients pharmaceutiquement acceptables qui ne réagissent pas de façon défavorable avec la duloxétine choisis parmi des diluants, des agglutinants et des agents désintégrants.
  5. La composition pharmaceutique à libération retardée de la revendication 4, dans laquelle l'agglutinant pharmaceutiquement acceptable est choisi parmi la hydroxypropylcellulose, l'amidon de maïs, la polyvinylpyrrolidone, l'hydroxylpropylméthylcellulose, l'hydroxyéthylcellulose et l'amidon prégélatinisé.
  6. La composition pharmaceutique à libération retardée de la revendication 4, dans laquelle l'agent désintégrant est choisi parmi la croscamellose de sodium, la crospovidone, le glycolate d'amidon de sodium et l'hydroxypropylcellulose faiblement substituée.
  7. La composition pharmaceutique à libération retardée de la revendication 1, dans laquelle la couche de médicament comprend de 15% à environ 40% de chlorhydrate de duloxétine, environ 30-80% de sphères de sucre, environ 2-10% d'hydroxypropylméthylcellulose, environ 0-10% d'hydroxypropylcellulose, environ 0-10% de saccharose extra fin, environ 1-10% de crospovidone et environ 1-10% de talc basé sur le poids de la couche de médicament.
  8. La composition pharmaceutique à libération retardée de la revendication 1, dans laquelle la couche de séparation comprend du saccharose, de l'hydroxypropylméthylcellulose et du talc.
  9. La composition pharmaceutique à libération retardée de la revendication 1, dans laquelle la couche de séparation est présente dans une quantité d'environ 5-30% basé sur le poids total de la formulation.
  10. La composition pharmaceutique à libération retardée de la revendication 1, dans laquelle la couche de séparation est présente dans une quantité d'environ 10-25% basé sur le poids total de la formulation.
  11. La composition pharmaceutique à libération retardée de la revendication 1, dans laquelle la couche entérique est présente dans une quantité d'environ 5-30% basé sur le poids total de la formulation.
  12. La composition pharmaceutique à libération retardée de la revendication 1, dans laquelle la composition comprend une couche de finition au-dessous de l'enrobage entérique.
  13. La composition pharmaceutique à libération retardée de la revendication 12, dans laquelle la couche de finition comprend de l'hydroxypropylméthylcellulose, du polyéthylène glycol, de l'oxyde de titane et du talc.
  14. La composition pharmaceutique à libération retardée de la revendication 1, dans laquelle la composition pharmaceutique à libération retardée de duloxétine est sous forme de pellets.
EP10852078.4A 2010-05-25 2010-05-25 Composition pharmaceutique à base de duloxétine destinée à la voie orale Not-in-force EP2575457B1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2010/000353 WO2011148380A1 (fr) 2010-05-25 2010-05-25 Composition pharmaceutique à base de duloxétine destinée à la voie orale

Publications (3)

Publication Number Publication Date
EP2575457A1 EP2575457A1 (fr) 2013-04-10
EP2575457A4 EP2575457A4 (fr) 2013-09-11
EP2575457B1 true EP2575457B1 (fr) 2016-08-17

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP10852078.4A Not-in-force EP2575457B1 (fr) 2010-05-25 2010-05-25 Composition pharmaceutique à base de duloxétine destinée à la voie orale

Country Status (6)

Country Link
US (1) US20130224290A1 (fr)
EP (1) EP2575457B1 (fr)
KR (1) KR20130071430A (fr)
CA (1) CA2799007A1 (fr)
ES (1) ES2601841T3 (fr)
WO (1) WO2011148380A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103393615B (zh) * 2013-07-24 2015-07-15 海南华益泰康药业有限公司 一种度洛西汀肠溶小丸及其制备方法
KR102242670B1 (ko) * 2014-01-09 2021-04-20 일동제약(주) 둘록세틴이 함유된 안정한 다중코팅 정제 조성물
JP2019081753A (ja) * 2017-10-30 2019-05-30 大原薬品工業株式会社 デュロキセチン塩酸塩の溶出性が改善された腸溶性製剤

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4547571A (en) * 1983-10-06 1985-10-15 Kohjin Co., Ltd. Process for preparing carboxymethyl ethyl cellulose suitable for enteric coating
US5508276A (en) * 1994-07-18 1996-04-16 Eli Lilly And Company Duloxetine enteric pellets
US20030096001A1 (en) * 2000-06-06 2003-05-22 Cherukuri S. Rao Encapsulation products and method of controlled release of fluoxetine or mesalamine
TW200639161A (en) * 2005-03-14 2006-11-16 Teva Pharma Process for the purification of duloxetine hydrochloride
EP1820800A1 (fr) * 2006-02-17 2007-08-22 KRKA, tovarna zdravil, d.d., Novo mesto Formes crystalline de l'hydrochlorure de duloxetine et procédés pour leur préparations
WO2008020286A2 (fr) * 2006-08-14 2008-02-21 Torrent Pharmaceuticals Limited Compositions pharmaceutiques de duloxétine
US20080226711A1 (en) * 2007-03-12 2008-09-18 Torrent Pharmaceuticals Ltd. Pharmaceutical compositions of duloxetine
WO2008129501A2 (fr) * 2007-04-20 2008-10-30 Wockhardt Research Centre Compositions pharmaceutiques de duloxetine
US20090226517A1 (en) * 2008-02-06 2009-09-10 Vinita Umashankar Vyas Pharmaceutical formulations comprising duloxetine
DE102009033621A1 (de) * 2009-07-17 2011-01-20 Add Technologies Ltd. Trennschichten für pharmazeutische Zubereitungen zur Verhinderung von Wechselwirkungen zwischen Arzneistoffen und pharmazeutisch-technologischen Hilfsstoffen

Also Published As

Publication number Publication date
WO2011148380A1 (fr) 2011-12-01
EP2575457A4 (fr) 2013-09-11
KR20130071430A (ko) 2013-06-28
ES2601841T3 (es) 2017-02-16
EP2575457A1 (fr) 2013-04-10
CA2799007A1 (fr) 2011-12-01
US20130224290A1 (en) 2013-08-29

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